Deciphering Tumor Metastasis and Immune Inhibitory Signature of Clear Cell Renal Cell Carcinoma by Single-Cell Transcriptome Analysis

Abstract

Clear cell renal cell carcinoma (ccRCC) is known for its high heterogeneity and tendency to metastasize through the bloodstream, leading to limited treatment options and poor overall survival rates. To overcome these challenges, it is crucial to acquire a comprehensive understanding of the underlying biology of ccRCC. Therefore, we conducted a thorough analysis using single-cell RNA sequencing data obtained from samples of non-metastatic and metastatic ccRCC. Our analysis revealed significant differences in the composition of infiltrating immune cells within the primary tumor lesions between metastatic and non-metastatic ccRCC cases. Additionally, we identified two distinct tumor cell states, particularly proximal tubule cells, which exhibited significant enrichment in metastatic ccRCC cases. We found that MDK was highly expressed in metastatic ccRCC and exhibited significant prognostic value for patients. In metastaic ccRCC, we observed enhanced interactions between tumor cells and macrophages mediated by MDK, resulting in the polarization of macrophages towards an angiogenic and immune-suppressive M2-like phenotype. Furthermore, we observed notable differences in the interactions between macrophages and CD8 + T cells in non-metastatic and metastatic ccRCC. Metastatic ccRCC exhibited stronger interactions mediated by immune inhibitory molecules such as SPP1 and CD24, potentially contributing to immune suppression within tumor microenvironment. These dignificant findings provide valuable insights into the molecular and cellular signatures associated with metastatic ccRCC. Moreover, they open up promising opportunities for the development of novel biomarkers and therapeutic targets, specifically tailored to address the challenges posed by metastatic ccRCC.